A TLR4-independent critical role for CD14 in intracellular LPS sensing.

Abstract

SUMMARYIntracellular lipopolysaccharide (LPS) sensing by the noncanonical inflammasome comprising caspase-4 or −11 governs antibacterial host defense. How LPS gains intracellular access in vivo is largely unknown. Here, we show that CD14—an LPS-binding protein with a well-documented role in TLR4 activation—plays a vital role in intracellular LPS sensing in vivo. By generating Cd14−/− and Casp11−/− mice strains on a Tlr4−/− background, we dissociate CD14’s known role in TLR4 signaling from its role in caspase-11 activation and show a TLR4-independent role for CD14 in GSDMD activation, pyroptosis, alarmin release, and the lethality driven by cytosolic LPS. Mechanistically, CD14 enables caspase-11 activation by mediating cytosolic localization of LPS in a TLR4-independent manner. Overall, our findings attribute a critical role for CD14 in noncanonical inflammasome sensing of LPS in vivo and establish—together with previous literature—CD14 as an essential proximal component of both TLR4-based extracellular and caspase-11-based intracellular LPS surveillance.